Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemia/reperfusion-associated translation inhibition in the hippocampus is attenuated significantly at reinitiation and elongation steps by ischemic preconditioning (Burda et al. [2003] Neurochem. Res. 28:1237-1243). To address potential regulation of the elongation step by changes in eukaryotic elongation factor 2 (eEF2) phosphorylation with and without acquired ischemic tolerance (IT), Wistar rats were preconditioned by 5-min sublethal ischemia and 2 days later, 30-min lethal ischemia was induced. Given the important role that oxidative stress plays in the ischemic process, eEF2 phosphorylation was also studied in a model of oxidative stress in vitro. Three blocks of our results support a lack of correlation between eEF2 phosphorylation status and protein synthesis rate. First, eEF2 was dephosphorylated significantly (activated) after transient cerebral ischemia in rats with and without IT or H2O2-treated cells; however, protein synthesis was significantly inhibited under these three conditions. Second, after 30-min reperfusion, the protein synthesis rate was maintained below control levels in cortex and hippocampus of rats without IT. Eukaryotic EF2 phosphorylated levels were notably low only in the cortex, whereas levels in the hippocampus were close to that of sham controls. In rats with IT, protein synthesis was virtually restored in both brain regions, but phosphorylated eEF2 levels were even higher than in rats without IT. Third, after 4-hr reperfusion, the protein synthesis rate in cortex and hippocampus was observed to be below sham control values in rats with and without IT. Conversely, phosphorylated eEF2 levels were below sham control in rats with IT and reached sham control values in rats without IT.
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PMID:Does phosphorylation of eukaryotic elongation factor eEF2 regulate protein synthesis in ischemic preconditioning? 1521 96

Excessive excitatory amino acid (EAA) release in cerebral ischemia is a major mechanism responsible for neuronal damage and death. A substantial fraction of ischemic EAA release occurs via volume-regulated anion channels (VRACs). Hydrogen peroxide (H2O2), which is abundantly produced during ischemia and reperfusion, activates a number of protein kinases critical for VRAC functioning and has recently been reported to activate VRACs. In the present study, we explored the effects of H2O2 on volume-dependent EAA release in cultured astrocytes, measured as the release of preloaded D-[3H]aspartate. 100-1,000 microm H2O2 enhanced swelling-induced EAA release by approximately 2.5-3-fold (EC50 approximately 10 microM). The VRAC blockers ATP, phloretin, and 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) potently inhibited both control swelling-induced and the H2O2-potentiated release, suggesting a role for VRACs. The H2O2-induced component of EAA release was attenuated by the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA-AM) and completely eliminated by the calmodulin antagonists trifluoperazine and W-7 and the Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor KN-93. Inhibitors of tyrosine kinases, protein kinase C, and the myosin light chain kinase were ineffective in blocking the H2O2 response. H2O2 treatment of swollen astrocytes, but not swelling alone, resulted in CaMKII activation that was inhibited by KN-93, as determined by a phospho-Thr286 CaMKII antibody. These data demonstrate that H2O2 strongly up-regulates astrocytic volume-sensitive EAA release via a CaMKII-dependent mechanism and in this way may potently promote pathological EAA release and brain damage in ischemia.
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PMID:Hydrogen peroxide potentiates volume-sensitive excitatory amino acid release via a mechanism involving Ca2+/calmodulin-dependent protein kinase II. 1556 71

CB1 cannabinoid receptors (CB1Rs) are involved in protecting the brain from ischemia and related disorders. However, the underlying protective mechanisms are incompletely understood. We investigated the effect of CB1R activation on oxidative injury, which has been implicated in neuronal death after cerebral ischemia and neurodegenerative disorders, in mouse cortical neuron cultures. The CB1R agonist Win 55212-2 [R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxazin-yl]-(1-naphthalenyl)methanone mesylate] reduced neuronal death, measured by lactate dehydrogenase release, in cultures treated with 50 microM FeCl2, and its protective effect was attenuated by the CB1R antagonist SR141716A [N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-cichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride]. The endocannabinoid anandamide reproduced the effect of Win 55212-2, as did the antioxidant 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox). Neuronal injury was more severe after in vitro or in vivo administration of FeCl2 to CB1R-knockout compared with wild-type mice. Win 55212-2 reduced the formation of reactive oxidative species in cortical neuron cultures treated with FeCl2, consistent with an antioxidant action. Pertussis toxin reduced CB1R-mediated protection, which points to a protective mechanism that involves signaling through G(i/o) proteins. Since CB1R-activated G protein signaling inhibits protein kinase A but activates phosphatidylinositol 3-kinase (PI3K), we tested the involvement of these pathways in CB1R-mediated neuroprotection. Dibutyryl-cyclic adenosine monophosphate (dbcAMP) blocked protection by Win 55212-2, whereas the PI3K inhibitor wortmannin did not, and the effect of dbcAMP was inhibited by the protein kinase A inhibitor H89 [N-[2-((p-bromocinnamyl)amino)ethyl]-5-isoquinolinesulfonamide] (> or =10 nM). CB1R-induced, SR141716A-, pertussis toxin-, and dbcAMP-sensitive protection was also observed for two other oxidative insults, exposure to H2O2 or buthionine sulfoximine. Therefore, receptor-stimulated inhibition of protein kinase A seems to be required for the neuroprotective effect of CB1R activation against oxidative neuronal injury.
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PMID:Involvement of protein kinase A in cannabinoid receptor-mediated protection from oxidative neuronal injury. 1562 18

We have previously identified an increased susceptibility of glutathione peroxidase-1 (Gpx1)-/- mice to neuronal apoptosis following mid-cerebral artery (MCA) occlusion. This study was designed to elucidate the mechanisms involved in elevated neuronal cell death arising from an altered endogenous oxidant state. This was addressed in both an in vitro and in vivo model of oxidative stress in the form of exogenous H2O2 and cerebral ischaemia, respectively. Increased levels of cell death were detected in primary neurons lacking Gpx1 following the addition of exogenous H2O2. This increased apoptosis correlated with a down-regulation in the activation of the phospho-inositide 3-kinase [PI3K]-Akt survival pathway. The importance of this pathway in protecting against H2O2-induced cell death was highlighted by the increased susceptibility of wildtype neurons to apoptosis when treated with the PI3K inhibitor, LY294002. The Gpx1-/- mice also demonstrated elevated neuronal cell death following MCA occlusion. Although Akt phosphorylation was detected in the Gpx1-/- brains, activation was not seen in later reperfusion events, as demonstrated in wildtype brains. Previous studies have highlighted the importance of Akt phosphorylation in protecting against neuronal cell death following cerebral ischaemia-reperfusion. Our results suggest that the increased susceptibility of Gpx1-/- neurons to H2O2-induced apoptosis and neuronal cell death in vivo following cerebral ischaemia-reperfusion injury can be attributed in part to diminished activation of Akt. Perturbations in key anti-apoptotic mechanisms as a result of an altered redox state may have implications in the study of oxidative stress-mediated neuropathologies.
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PMID:Diminished Akt phosphorylation in neurons lacking glutathione peroxidase-1 (Gpx1) leads to increased susceptibility to oxidative stress-induced cell death. 1566 76

Ethyl pyruvate (EP) is a pyruvate derivative, and has recently been reported to prevent lethality in mice with established lethal sepsis and systemic inflammation. In a previous study, we reported that EP has a neuroprotective effect in a rat cerebral ischemia model of middle cerebral artery occlusion (MCAO), in which it was found to be effective when injected as late as 12 h after MCAO/reperfusion. In the present study, we show that therapeutic window of pyruvate in this MCAO animal model is limited to 1 h (30 min before and 30 min after MCAO). Moreover, both pyruvate and EP have a neuroprotective effect during oxygen-glucose deprivation (OGD) or H2O2 challenge in primary cortical culture. In contrast, EP suppressed the LPS-induced activation of primary microglia in culture, but pyruvate did not. The suppression of microglia activation was evidenced by a reduction in nitric oxide release and by a proinflammatory factor induction in primary microglia culture, which were accompanied by the repression of nuclear factor-kappaB activation. These results suggest that EP has a strong protective effect and a wide therapeutic window, and that this protective effect of EP is related to its anti-inflammatory action.
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PMID:Anti-inflammatory mechanism is involved in ethyl pyruvate-mediated efficacious neuroprotection in the postischemic brain. 1622 31

Hydroxyhydroquinone or 1,2,4-benzenetriol (BT) detected in the beverages has a structure that coincides with the water-soluble form of a sesame lignan, sesamol. We previously showed that sesame antioxidants had neuroprotective abilities due to their antioxidant properties and/or inducible nitric oxide synthase (iNOS) inhibition. However, studies show that BT can induce DNA damage through the generation of reactive oxygen species (ROS). Therefore, we were interested to investigate the neuroprotective effect of BT in vitro and in vivo. The results showed that instead of enhancing free radical generation, BT dose-dependently (10-100 microM) attenuated nitrite production, iNOS mRNA and protein expression in lipopolysaccharide (LPS)-stimulated murine BV-2 microglia. BT significantly reduced LPS-induced NF-kappaB and p38 MAPK activation. It also significantly reduced the generation of ROS in H2O2-induced BV-2 cells and in H2O2-cellfree conditions. The neuroprotective effect of BT was further demonstrated in the focal cerebral ischemia model of Sprague-Dawley rat. Taken together, the inhibition of LPS-induced nitrite production might be due to the suppression of NF-kappaB, p38 MAPK signal pathway and the ROS scavenging effect. These effects might help to protect neurons from the ischemic injury.
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PMID:Protective effect of 1,2,4-benzenetriol on LPS-induced NO production by BV2 microglial cells. 1630 62

Oxidative stress induced cell injury is reported to contribute to the pathogenesis of cerebral ischemia. Reactive oxygen species such as hydrogen peroxide (H2O2) and superoxide radical along with nitric oxide and peroxynitrite generated during ischemia-reperfusion injury, causes the overactivation of poly (ADP-ribose) polymerase (PARP) leading to neuronal cell death. In the present study we have evaluated the effects of PARP inhibitor, 8-hydroxy-2 methyl-quinazolin-4-[3H]one (NU1025) in H2O2 and 3-morphilinosyndonimine (SIN-1) induced cytotoxicity in PC12 cells as well as in middle cerebral artery occlusion (MCAO) induced focal cerebral ischemia in rats. Exposure of PC12 cells to H2O2 (0.4 mM) and SIN-1 (0.8 mM) resulted in a significant decrease in cell viability after 6 h. Pretreatment with NU1025 (0.2 mM) restored cell viability to approximately 73 and 82% in H2O2 and SIN-1 injured cells, respectively. In MCAO studies, NU1025 was administered at different time points (1 h before reperfusion, immediately before reperfusion, 3 h after reperfusion and 6 h after reperfusion). NU1025 at 1 and 3 mg/kg reduced total infarct volume to 25% and 45%, respectively, when administered 1 h before reperfusion. NU1025 also produced significant improvement in neurological deficits. Neuroprotection with NU1025 was associated with reduction in PAR accumulation, reversal of brain NAD depletion and reduction in DNA fragmentation. Results of this study demonstrate the neuroprotective activity of NU1025 and suggest its potential in cerebral ischemia.
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PMID:Neuroprotective effects of NU1025, a PARP inhibitor in cerebral ischemia are mediated through reduction in NAD depletion and DNA fragmentation. 1693 10

Breviscapine, a traditional Chinese medicine, is extensively used in clinic to treat cardiovascular diseases and cerebrovascular injury. In this study, we demonstrated the effects of breviscapine on vascular dementia (VD) rats, which were mimicked by permanent occlusion of bilateral common carotid arteries. Breviscapine (2 mg/kg for 14 d) improved the performance of learning and memory of VD rats in Morris water maze, decreased the level of lipid peroxidation and free radicals, and attenuated the pathological alterations, such as nuclear shrink, cellular edema and irregular arrangement of pyramidal layer in the hippocampal CA(1) area. In vitro experiment, breviscapine (50 microg/l) protected cortical neuron from injury and decreased intracellular calcium overloading induced by H2O2 (10 mM). The results suggest that breviscapine has therapeutic effect on cerebral ischemia and vascular dementia.
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PMID:Protective effects of breviscapine on ischemic vascular dementia in rats. 1694 2

Aberrant oxidation of norepinephrine (1) via the transient o-quinone has been implicated as a critical pathogenetic mechanism underlying the degeneration of noradrenergic cell bodies in the locus coeruleus in Parkinson's disease, the degeneration of noradrenergic nerve terminals in Alzheimer's disease and following transient cerebral ischemia, and the onset and progression of idiopathic vitiligo. An oxidative pathway of 1 is also believed to account for the slow deposition of neuromelanin in pigmented neurons of the locus coeruleus. Remarkably, after extensive investigations spanning over several decades, there is still a lack of knowledge of the oxidation chemistry of 1 beyond the classic cyclization route leading to aminochrome and lutin intermediates. We report herein that oxidation of 1 in the 50-500 microM concentration range with H2O2-dependent oxidizing agents, such as the Fenton reagent (Fe2+-EDTA/H2O2) and the horseradish peroxidase (HRP)/H2O2 system, leads not only to the known cyclization products, such as noradrenochrome and 5,6-dihydroxyindole (3), but also to a significant proportion of chain breakdown products, including 3,4-dihydroxybenzaldehyde, 3,4-dihydroxybenzoic acid, 3,4-dihydroxymandelic acid, and 3,4-dihydroxyphenylglyoxylic acid, which has never been described among the oxidation products or metabolites of 1. Analysis of the brown melanin-like pigment obtained by oxidation of 1 with HRP/H2O2 gave pyrrole-2,3-dicarboxylic acid and pyrrole-2,3,5-tricarboxylic acid, diagnostic markers of 3-derived units in eumelanins. Comparison with reference pigments prepared by similar oxidation of dopamine and 3 indicated that in the case of 1 oxidative polymerization of indole units through the 2-position contributes only to a minor extent to melanin formation. Overall, the results of this study provide a complete characterization of the oxidative chain fission pathways of 1, highlight 3,4-dihydroxyphenylglyoxylic acid as a novel possible metabolic product of this catecholamine, and yield an insight into norepinephrine-melanin, a putative component of locus coeruleus neuromelanin.
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PMID:Oxidation chemistry of norepinephrine: partitioning of the O-quinone between competing cyclization and chain breakdown pathways and their roles in melanin formation. 1789 64

AlphaB-crystallin, known as a vertebrate lens protein, is a member of the small heat shock proteins (sHSP). AlphaB-crystallin is abundantly expressed in the vertebrate lens and striated muscles and it is also expressed constitutively in other tissues including the central nervous system (CNS). In our previous report, we showed alphaB-crystallin induction in activated astrocytes, which are enriched in the penumbra after transient focal cerebral ischemia. We also reported that alphaB-crystallin is significantly induced in astrocytes in the CA3 region of the hippocampus following KA-induced seizure. Here, we report that the expression of alphaB-crystallin is upregulated in H2O2-treated primary astrocyte cultures, which was prepared from newborn male Sprague-Dawley rats and that the proximal 408 bp of the alphaB-crystallin promoter harboring stress response element (STRE) is responsible for this induction. This effect of H2O2 was found to be virtually abolished by introducing mutations into STRE, and these mutations also impaired increased lens epithelial derived growth factor (LEDGF) binding to STRE after H2O2 treatment. Moreover, LEDGF was induced in primary astrocyte cultures after H2O2 treatment and alphaB-crystallin induction was significantly suppressed by transfecting small interfering RNA (siRNA) targeting LEDGF. Together these results indicate that the H2O2-induced upregulations of alphaB-crystallin in astrocytes are mediated by the LEDGF-STRE interaction on alphaB-crystallin promoter.
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PMID:LEDGF binding to stress response element increases alphaB-crystallin expression in astrocytes with oxidative stress. 1834 76


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